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- Title
Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice.
- Authors
Denny, Christine A.; Heinecke, Karie A.; Kim, Youngho P.; Baek, Rena C.; Loh, Katrina S.; Butters, Terry D.; Bronson, Roderick T.; Platt, Frances M.; Seyfried, Thomas N.
- Abstract
J. Neurochem. (2010) 113, 1525–1535. Sandhoff disease is an autosomal recessive, neurodegenerative disease involving the storage of brain ganglioside GM2 and asialo-GM2. Previous studies showed that caloric restriction, which augments longevity, and N-butyldeoxynojirimycin ( NB-DNJ, Miglustat), an imino sugar that hinders the glucosyltransferase catalyzing the first step in glycosphingolipid biosynthesis, both increase longevity and improve motor behavior in the β-hexosaminidase ( Hexb) knockout (−/−) murine model of Sandhoff disease. In this study, we used a restricted ketogenic diet (KD-R) and NB-DNJ to combat ganglioside accumulation. Adult Hexb−/− mice were placed into one of the following groups: (i) a standard diet (SD), (ii) a SD with NB-DNJ (SD + NB-DNJ), (iii) a KD-R, and (iv) a KD-R with NB-DNJ (KD-R + NB-DNJ). Forebrain GM2 content (μg sialic acid/100 mg dry wt) in the four groups was 375 ± 15, 312 ± 8, 340 ± 28, and 279 ± 26, respectively, indicating an additive interaction between NB-DNJ and the KD-R. Most interestingly, brain NB-DNJ content was 3.5-fold greater in the KD-R + NB-DNJ mice than in the SD + NB-DNJ mice. These data suggest that the KD-R and NB-DNJ may be a potential combinatorial therapy for Sandhoff disease by enhancing NB-DNJ delivery to the brain and may allow lower dosing to achieve the same degree of efficacy as high dose monotherapy.
- Subjects
KETOGENIC diet; DIET in disease; TAY-Sachs disease; NEURODEGENERATION; LABORATORY mice; SANDHOFF disease
- Publication
Journal of Neurochemistry, 2010, Vol 113, Issue 6, p1525
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2010.06733.x